Treatment of osteoporosis, metastatic bone disease, and Paget's disease can benefit from combinations of treatment modalities. These diseases are commonly treated with bis-phosphonates while osteoporosis is also commonly treated with hormone replacement therapy or with selective estrogen receptor modulators. Bis-phosphonates such as alendronate, risedronate, etidronate, zoledronic acid, and tiludronate are commonly prescribed drugs for treatment of these diseases. Despite their benefits, bis-phosphonates suffer from very poor oral bioavailability. Alendronate has less than 1% bioavailability. Gert et al., “Studies of The Oral Bioavailability of Alendronate,” Clinical Pharmacology & Therapeutics, 1995, 58, 288-298. Alendronate's absorption is inhibited by foods and beverages other than water. Id. When not following the recommended dosing instructions, patients taking alendronate have experienced irritation of the upper gastrointestinal mucosa. Liberman et al., “Esophagitis and Alendronate,” N. Engl. J Med., 1996, 335, 1069-70. In rare instances, the irritation associated with the administration of alendronate can be serious. See, FOSAMAX® Warnings, PHYSICIAN'S DESK REFERENCE, pp. 1996-2003 (57th Ed., 2003).
While there are some indications that among the bis-phosphonates, alendronate does not cause ulceration, some literature indicate that alendronate shares this feature with the other bis-phosphonates. See, D. C. Bauer et. al., “Upper gastrointestinal tract safety profile of alendronate: the fracture intervention trial,” Arch. Intern. Med., 2000, 160(4), 517-25; Marshall et. al., “A randomized controlled trial to assess alendronate-associated injury of the upper gastrointestinal tract,” Aliment. Pharmacol. Ther., 2000, 14(11), 1451-7; Graham et al., “Alendronate gastric ulcers,” Aliment. Pharmacol. Ther., 1999, 13(4), 515-9; S. C. Abraham et. al., “Alendronate-associated esophageal injury: pathologic and endoscopic features,” Mod. Pathol., 1999, 12(12), 1152-7; Elliott et. al., “Alendronate induces gastric injury and delays ulcer healing in rodents,” Life Sci., 1998, 62(1), 77-91; D. Y. Graham, “Excess gastric ulcers are associated with alendronate therapy,” Am. J. gastroenterol., 1998, 93(8), 1395-6; and Colina et. al., “A new probable increasing cause of esophageal ulceration: alendronate,” Am. J. Gastroenterol., 1997, 92(4), 704-6.
The mechanism of the cause of esophagitis and/or gastritis is not always known, and sometimes it is intrinsic to the chemistry of the particular drug. However, in the case of NSAIDs, bis-phosphonates, and other drugs, there is evidence that implicates contact with the solid form of the drug with ulceration. D. Jasperson, “Drug induced esophageal disorders: pathnogenesis, incidence, prevention and management,” Drug Saf., 2000, 22(3), 237-249; Smith et. al., “Pill-induced esophagitis caused by oral rifampin,” Ann. Pharmocother., 1999, 33(1), 27-31; J. W. Kikendall, “Pill esophagitis,” J. Clin. Gastroenterol., 1999, 28(4), 298-305. Such esophagitis is called pill induced esophagitis or pill esophagitis, and contact gastritis when there is damage to the stomach lining. These forms of mucosal damage can be mitigated by preventing the physical contact of the drug contained in a solid dose formulation with the surface of the mucosa.
Alendronate is best absorbed from in the upper gastrointestinal (GI) tract (duodenum and jejunum). Lin, J. H. “Bisphosphonates: A Review of Their Pharmacokinetic Properties,” Bone, 1996, 18, 75-85; Porras et al., “Pharmacokinetics of Alendronate,” Clin. Pharmacokinet., 1999, 36, 315-328. Alendronate is best absorbed at a pH of ˜6. Gert et al., “Studies of The Oral Bioavailability of Alendronate,” Clinical Pharmacology & Therapeutics, 1995, 58, 288-298.
In addition to bis-phosphonate therapy, options in the treatment of osteoporosis include hormone replacement therapy and calcium supplementation therapy. Kleerekoper et al., “Comparative Safety of Bone Remodeling Agents with A Focus on Osteoporosis Therapies,” J. Clin. Pharmacol., 2001, 41, 239. Increased calcium levels can potentially improve the state of bone mineralization in patients with osteoporosis. Over the last thirty years, calcium supplementation, along with vitamin D or vitamin D derivatives such as calcitriol, has been one of the options for treating the problems of osteoporosis. Cannigia et al., “Effects of 1,25-Dihydroxycholecalciferol on Calcium Absorption in Postmenopausal Osteoporosis,” Clin. Endocrinol., 1979, 11, 99; Riggs et al., “Effect of Long Term Treatment with Calcitriol on Calcium Absorption and Mineral Metabolism in Postmenopausal Osteoporosis,” J. Clin. Endocrinol. Metab., 1985, 61, 457; Reid et al., “Long Term Effects of Calcium Supplementation on Bone Loss and Fracture in Post-menopausal Women, a Randomized Controlled Trial,” Am. J. Med., 1995, 98, 331. Calcitriol (1,25-dihydroxyvitamin D3) is a vitamin D derivative that is active in the regulation of the absorption of calcium from the gastrointestinal tract. See, Rocaltrol Oral Solution, Description, PHYSICIAN'S DESK REFERENCE, pp. 2914-2916 (57th Ed., 2003). Calcitriol is the biologically active form of vitamin D3 and stimulates intestinal calcium transport. MERCK INDEX, pp. 1681-1682 (12th Ed. 1997). Calcitriol is used to treat calcium deficiency.
Over the past several years, successful trials have been performed that confirm that there is a synergistic effect in using a combined therapy of calcitriol and bis-phosphonates. Frediani et al., “Effects of Combined Treatment with Calcitriol Plus Alendronate on Bone Mass and Bone Turnover in Postmenopausal Osteoporosis—Two Years of Continuous Treatment,” Clin. Drug Invest., 1998, 15, 223; Masud et al., “Effects of Cyclical Etidronate Combined with Calcitriol Versus Cyclical Etidronate Alone on Spine and Femoral Neck Bone Mineral Density in Postmenopausal Women,” Ann. Rheum. Dis., 1998, 57, 346; Malvolta et al., “Calcitriol and Alendronate Combination Treatment in Menopausal Women with Low Bone Mass,” Int. J. Tissue React., 1999, 21, 51; Nuti et al., “Effect of Treatment with Calcitriol Combined with Low-dosage Alendronate in Involutional Osteoporosis,” Clin. Drug Invest., 2000, 19, 56. The goal of the combined therapy trials is to improve therapeutic results and lower the dosage of the two drugs. In these trials the drugs were given individually. International Publication WO 2001/028564 discloses a tablet containing a combination of calcitriol and alendronate in a particular drug ratio range.
Another mode of treatment of osteoporosis is the use of hormone receptor modulators. Raloxifene (Evista®, Eli Lilly), a selective estrogen receptor modulator (SERM), is a benzothiophene non-steroidal estrogen antagonist related to tamoxifen, and is indicated for the prevention and treatment of osteoporosis in post-menopausal women. PHYSICIAN'S DESK REFERENCE, pp. 1717-1721 (55th Ed., 2001).
Decreases in estrogen levels after menopause lead to increases in bone resorption and accelerated bone loss. Raloxifene's activity is mediated by its selective binding to certain estrogen receptors, thus activating or blocking various estrogenic pathways, thereby offsetting the estrogen-induced bone loss. As a result, raloxifene has been shown to increase bone density in the spine and hip, and reduce bone turnover, thus significantly decreasing the incidence of new vertebral fractures by 30-50% among post-menopausal women with osteoporosis. Id. Raloxifene is absorbed rapidly after oral administration. Approximately 60% of the oral dose is absorbed, but due to extensive presystemic glucuronide conjugation (to the metabolites, raloxifene-4-glucuronide, raloxifene-6-glucuronide and raloxifene-6,4-diglucuronide), the oral bioavailability of raloxifene is only 2%.
The combination of hormone receptor modulators and bis-phosphonates has been studied. A study of bone mineral density of one year treatment with alendronate alone, raloxifene alone or the two drugs in combination, showed improved results for the drug combination when compared to either mono-therapy. When dosing 60 mg/day of raloxifene, 10 mg/day of alendronate, or the combined drugs delivered separately in separate dosage forms in 331 patients with osteoporosis for 1 year, improvements in femoral bone mass density were observed for all groups with the combined treatment showing an improvement of 3.7% compared to 2.7% for alendronate alone (P=0.02) and 1.7% for raloxifene alone (P=0.001). Other markers demonstrated improvement in the combination treatment when compared to either treatment alone but did not reach statistical significance when compared to the alendronate alone. O. Johnell et. al. “Additive Effects of Raloxifene and Alendronate on Bone Density and Biochemical Markers of Bone Remodeling in Postmenopausal women with Osteoporosis,” J. Clin. Endocrinol. Metab., 2002, 87(3), 985-992.
Although the combination of raloxifene and alendronate demonstrated improved osteoporosis treatment, there is a need for increased dosages of bis-phosphonates in the combination therapy. The invention addresses this need by providing a formulation which mitigates the ulcerative adverse events associated with mucosal contact with bis-phosphonates.